The role of TMEM163 protein in thyroid microcarcinoma: expression pattern and clinical implications.

BACKGROUND: TMEM163 protein is a new zinc ion transporter whose regulatory role in tumors has yet to be discovered. This study aimed to analyze the expression pattern of TMEM163 in thyroid microcarcinoma and explore its potential molecular function and clinical value. METHODS: Differential analysis was performed to detect the expression pattern of TMEM163 in papillary thyroid carcinoma. Functional analysis was performed to explore the biological function of TMEM163. Logistic regression was performed to detect the relationship between TMEM163 expression and lymph node metastasis. A correlation analysis of the relationship between 163 and anoikis was performed. qRT-PCR and western blot were used to verify its expression in PTC tissues. The effect of TMEM163 on PTC cell function was studied by a series of in vitro cell experiments. The prediction model of lymph node metastasis was constructed based on the ultrasonic characteristics of PTMC and the expression of TMEM163. RESULTS: The expression of TMEM163 in PTC tissue was higher than in normal thyroid tissue. In vitro, silencing TMEM163 inhibited PTC cells' proliferation, migration, and invasion, while TMEM163 overexpression exhibited the opposite effect. In addition, down-regulating its expression can inhibit the cell cycle process and induce the apoptosis of tumor cells. In pathway analysis, we demonstrated that knockout of TMEM163 significantly increased p21 expression and inhibited BCL-2 expression. Logistic regression results suggested that the expression of TMEM163 combined with PTMC ultrasound characteristics helped predict lymph node metastasis. CONCLUSION: TMEM163 is highly expressed in PTC, which may be involved in the mechanism of anoikis, and can be used as a molecular marker to predict PTMC lymph node metastasis.

Cholecystokinin regulates atrial natriuretic peptide secretion through activation of NOX4-Sirt1-LEF1 signaling in beating rat hypoxic atria.

The mammalian cardiac myocytes not only synthesize and secrete atrial natriuretic peptide (ANP), but also express cholecystokinin (CCK) and its receptors (CCK1R and CCK2R). However, atrial CCK expression patterns and its effects on ANP secretion during hypoxia are unclear. Therefore, this study is aimed to investigate the effect of hypoxia on the expression levels of CCK and its receptors, as well as the underlying mechanisms involved in regulating hypoxia-induced ANP secretion in isolated beating atria. The results of this study showed that acute hypoxia significantly upregulated expression of CCK and CCK1R as well as CCK2R through activation of hypoxia-inducible factor 1α-apelin signaling. Endogenous CCK induced by hypoxia markedly upregulated the expression of silent information regulator factor 2-related enzyme 1 (Sirt1) and its downstream nuclear factor erythroid­2­related factor 2 (Nrf2) via the activation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), leading to increase of activating T cell factor (TCF) 3 and TCF4/ lymphoid enhancer factor (LEF) 1, ultimately promoting hypoxia-induced ANP secretion. In addition, siRNA-mediated knockdown of LEF1 dramatically attenuated hypoxia-induced increase of ANP expression in HL-1 atrial myocytes. These results indicated endogenous CCK induced by hypoxia promoted hypoxia-induced ANP secretion by activation of NOX4-Sirt1-TCF3/4-LEF1 signaling pathway.

Effects of a Novel Magnetic Nanomaterial on Oral Biofilms.

Dental caries is one of the most common oral chronic infectious diseases, and novel antibacterial materials must be developed to control plaque and inhibit formation of dental caries. Combining magnetic nanomaterials with antibacterial agents to decrease the formation of bacterial biofilm has been a hot topic in the biomedical field. The present study developed a novel magnetic nanomaterial chemically combined with dimethylaminododecyl methacrylate (DMADDM) and initially investigated its inhibiting effects on biofilms by using traditional caries-related bacteria and saliva flora models. The novel magnetic nanomaterials successfully loaded DMADDM according to thermogravimetric analysis, Fourier transform infrared spectroscopy, x-ray diffraction, vibrating sample magnetometry, scanning electron microscopy, and transmission electron microscopy results. Further, the novel nanoparticle Fe3O4@SiO2@DMADDM with concentration of 8 mg/mL could effectively reduce Streptococcus mutans biofilm and decrease the production of lactic acid. The 16S rDNA sequencing revealed that Fe3O4@SiO2@DMADDM could depress the proportion of caries-related bacteria in saliva-derived biofilm, such as Streptococcus, Veillonella, and Neisseria. Therefore, Fe3O4@SiO2@DMADDM is a novel effective antibacterial magnetic nanomaterial and has clinical potential in plaque control and dental caries prevention.

Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.

Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.

Functional determination of site-mutations in rdxA involved in metronidazole resistance of Helicobacter pylori.

Background: Metronidazole (MTZ) is among the first-line drugs against the human gastric pathogen Helicobacter pylori (H. pylori). MTZ is used as a prodrug that is activated by an oxygen-insensitive enzyme NADPH nitroreductase (RdxA). Loss-of-function mutations in rdxA make H. pylori MTZ resistant; however, experimental proof is lacking. Methods: We collected 139 gastric biopsy samples from patients suspected of H. pylori infection in Shanghai, and amplified Hp-specific rdxA gene from 134 samples. All these rdxA genes were sequenced and phylogenetically compared. The effect of mutations on RdxA function was measured by expressing them in Escherichia coli DH5α by using the MTZ sensitivity test. Results: In total, 134 gastric biopsy samples were identified as H. pylori positive. Of the 134 samples, 74 and 6 had point mutations at the various sites or promoter region of rdxA, generating truncated and extended fused proteins, respectively. The remaining 54 were full-length with single nucleotide variation (SNV) compared with the wild-type RdxA from H. pylori, with 49 clustering with hpEastAsia, 3 with hpEurope, and 2 with hpNEAfrica. All 134 rdxA were expressed in E. coli DH5α; 22 and 112 resultant strains showed MTZ-sensitive and MTZ-resistant phenotypes, respectively. Comparative analysis of single nucleotide polymorphisms (SNPs) in the functional and inactivated RdxA revealed 14 novel mutations in RdxA, 5 of which conferred MTZ resistance: S18F, D59S, L62I, S79N, and A187V. Conclusion: The occurrence of MTZ resistance induced by site-mutation of RdxA in patients with H. pylori infection was 83.6% (112/134) in the Shanghai region. The major form of loss-of-function mutation was truncation of RdxA translation at a rate of 58/112 (51.8%). Molecular detection reliably determined the resistance of H. pylori to MTZ. Thus, the functional mutants involved in MTZ resistance facilitate clinical diagnosis and medication based on sequence analysis.

Association between waist triglyceride index, body mass index, dietary inflammatory index, and triglyceride- glucose index with chronic kidney disease: the 1999-2018 cohort study from NHANES.

Purpose: To compare the dietary inflammatory index (DII), triglyceride glucose index (TyG), waist triglyceride index (WTI), and body mass index (BMI) in predicting the survival of chronic kidney disease (CKD). Methodology: Inclusion of 23,099 participants from the NHANES database who met specific criteria. Baseline was established using quartiles of DII index. The relationship between DII index, WTI index, TyG index, and BMI index with mortality rate in CKD patients was evaluated using Kaplan-Meier curves. Univariate and multivariate COX regression risk models were used to study the relationship between DII index, WTI index, and TyG index with mortality risk in CKD patients. Stratification of eGFR by age and gender was conducted to investigate the association between DII index, WTI index, and TyG index with mortality risk in CKD patients. Restricted cubic spline analysis was used to study the correlation between DII index, WTI index, and TyG index with mortality risk in CKD patients. Results: The incidence of CKD increased with the increase of DII index, WTI index and TyG index. After multivariable adjustment, the fourth quartile of DII index, TyG index and WTI index showed the highest risk for CKD [DII: hazard ratio (HR) 1.36, 95% confidential interval (CI) (1.23-1.51); TyG: HR 1.21; 95% CI (1.07-1.37); WTI: HR 1.29; 95% CI (1.13-1.46)]. There was no difference in the risk of developing CKD between the obese group (BMI ≥24 kg/m2) and the normal weight group (P>0.05). Conclusion: This study has identified a significant association between elevated DII index, WTI index, and TyG index with the risk of CKD. Furthermore, the DII index demonstrated superior prognostic capability in predicting CKD compared to other indicators.

Efficacy and safety of the traditional Chinese formula Shengjiang powder combined with conventional therapy in the treatment of diabetic kidney disease: a systematic review and meta-analysis.

Objective: To investigate the efficacy and safety of Shengjiang powder as a treatment for DKD. Methods: A comprehensive search was performed in eight databases from their inception to December 30, 2023, to identify relevant RCTs. The inclusion criteria were diagnosis of DKD and intervention including TCM that contained Shengjiang powder. Two researchers independently conducted literature screening and data extraction, utilizing the Rob2 tool and GRADE to assess the quality of the RCTs. Meta-analysis was carried out using RevMan 5.4.1 and Stata 15.0. Results: As a result of the search, 23 RCTs comprising 1,682 patients. The interventions resulted in significant reductions in all the assessed indicators: 24-h urinary protein, UAER, mALB, BUN, Scr, FBG, 2hPG, HbA1c, total cholesterol, and Triglycerides. Together the results showed that Shengjiang powder, in conjunction with conventional therapy, is an effective treatment of DKD. Subgroup analyses, considering duration, stage, blood glucose control levels, baseline blood glucose levels, and baseline Scr levels indicated that shorter duration treatment had a greater effect on UAER, 2hPG, and HbA1c. Additionally, Shengjiang powder was more effective in reducing 24-h urinary protein, Scr, and 2hPG in stage IV patients compared to corresponding values at other stages. However, with respect to FBG, the treatment was more effective in stage II/III. Shengjiang powder also, reduced Scr levels significantly in patients with higher baseline Scr and reduced urinary protein excretion with stricter blood glucose control. The interventions had additional lipid-regulating effects in cases with looser blood glucose control and led to a remarkable reduction in BUN and Scr levels in patients with FBG > 11.1 mmol/L. Conclusion: Shengjiang powder may supplement conventional therapy, thus benefiting DKD patients in terms of reducing urinary protein, stabilizing kidney function, and improving blood glucose and lipid metabolism. Considering the significant heterogeneity among studies and limited quality of some reports, our conclusions need to be further verified through analyses utilizing larger, multi-center samples of higher quality. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024490795.

Synthesis and biological studies of 2-aminothiophene derivatives as positive allosteric modulators of glucagon-like peptide 1 receptor.

As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 µM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.

Earmuff performance in the presence of high-level impulse from a recoilless weapon firing in a confined space.

A noise attenuation performance test was conducted on earmuffs using a recoilless weapon launch platform in a confined space, along with two acoustic test fixtures (ATFs). The overpressure at the ATF's effective tympanic membrane comprised direct sound at 185 dB sound pressure level (SPL) and reflected sound at 179 dB SPL. Wearing earmuffs reduced these peaks to 162 dB SPL and 169 dB SPL, respectively. The reflected sound from walls was defined as delayed sound. An analytical model for earmuff noise attenuation simulated their effectiveness. The simulation revealed that when the earmuffs attenuated delayed sound, the acoustic impedance of acoustic leakage and the acoustic impedance of the earmuff material decreased by 96% and 50%, respectively. The negative overpressure zone between direct and delayed sound decreased the earmuffs' fit against the ATF. Additionally, the enclosed volume between the earmuff and the ear canal decreased by 12%. After the installation of bandages on the earmuffs, the overpressure peak of delayed sound was reduced by 5 dB. Furthermore, the acoustic impedance of the earmuff's sound leakage path and the acoustic impedance of the earmuff material deformation path increased by 100% and 809%, respectively.

Inhibitors and PROTACs of CDK2: challenges and opportunities.

INTRODUCTION: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors. AREA COVERED: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments. EXPERT OPINION: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.